The main goal of this proposal is to design lipophilic anti-AIDS nucleosides for the treatment of patients with AIDS-related complexes. AIDS dementia complex (ADC) is the leading cause of mental health damage in AIDS patients with advanced stage of human immunodeficiency virus (HIV) infection. The available anti-HIV nucleosides such as 3'- azidothymidine (AZT), when given to AIDS patient, either do not cross the blood-brain barrier (BBB) or cross to a very small extent. In order to overcome this problem, we propose to develop lipophilic analogs of anti-HIV nucleosides for improved brain delivery by two mechanisms, 1) by designing lipophilic derivatives of anti-HIV nucleosides and 2) by linking active nucleoside to a dihydropyridine carrier. In this regard, a recent report on anti-HIV activity of C6-substituted acyclouridines has shown that introduction of a hydrophobic thiophenyl function at C6 position of pyrimidine base results in potent anti-HIV activity and increased lipophilicity. Following this lead, we have designed C6- thiophenyl substituted derivatives of 3'-azidopyrimidine, 2',3'- dideoxypyrimidines and 2',3'-didehydo-2',3'-dideoxypyrimidines as potential lipophilic anti-HIV agents. Earlier, we have reported acyclic unsaturated nucleoside analogs with potent anti-HIV activity, therefore, we also propose to develop C6-thiophenyl unsaturated acyclopyrimidines as isosteric analogs of acyclouridines. The proposed target analogs will be synthesized by known synthetic routes and will be evaluated for their anti-HIV activity. To achieve higher concentrations of most active agents in brain, these nucleosides will be coupled with dihydropyridine carrier to improve their delivery to CNS, and thereby stopping further neurological damage caused by HIV replication. The promising agents will be further studied for their brain deposition, CSF transfer and bioavailability in NIH-Swiss mice.